Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca2+). Changes in the concentration of extracellular Ca2+ (referred to herein as “[Ca2+]”) alter the functional responses of these cells. One such specialized cell is the parathyroid cell which secretes parathyroid hormone (PTH). PTH is the principal endocrine factor regulating Ca2+ homeostasis in the blood and extracellular fluids.
PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the blood. This increase in [Ca2+] then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between [Ca2+ ] and PTH secretion forms the essential mechanism maintaining bodily Ca2+ homeostasis.
Extracellular Ca2+ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in [Ca2+] has been confirmed (see Brown et al., Nature 366:574, 1993). In parathyroid cells, this protein, the calcium sensing receptor, acts as a receptor for extracellular Ca 2+, detects changes in the ion concentration of extracellular Ca2+, and initiates a functional cellular response, PTH secretion.
Extracellular Ca2+ influences various cell functions, as reviewed in Nemeth et al., Cell Calcium 11:319, 190. Specifically, the osteoclast in bone, the juxtaglomerular, proximal tubule cells in the kidney, the keratinocyte in the epidermis, the parafollicular cell in the thyroid, intestinal cells, and the trophoblast in the placenta, have the capacity to sense changes in [Ca2+ ]. It has been suggested that cell surface calcium sensing receptors may also be present on these cells, imparting to them the ability to detect and to initiate or enable a response to changes in [Ca2+].
Accordingly, compounds which mimic the effects of extracellular Ca2+ on a calcium sensing receptor molecule may be useful as calcium modulators which are active at Ca2+ receptors. Such compounds could be useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypetides, such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca2+ receptors. Target diseases or disorders for these compounds include diseases involving abnormal bone and mineral homeostasis.
Abnormal calcium homeostasis may be characterized by one or more of the following activities: abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels, such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
In extensive animal experiments and in clinical trials, intermittent injection of low doses of PTH has been shown to be a safe and effective stimulator of bone formation (see Whitfiled J F, et al. (2002) Treat Endocrinol (2002) 1(3):175-190). A double blind, randomized, placebo-controlled trial in postmenopausal women, the PTH peptide fragment (1-34) was shown to reduce the risk of spine fractures and non-traumatic, non-spine fractures 65% and 54%, respectively (Neer R M, et al. (2001) N Engl J Med 344:1434-1441.). In contrast to the anabolic effects observed after intermittent administration, it is well documented that continuous exposure to the hormone results in increases in bone turnover with a subsequent loss in bone mass.
Other than applying a PTH peptide fragment, conceivably, one could make use of the endogenous stores of PTH in the parathyroid gland, in order to stimulate bone formation through the release of PTH.
Proof-of-principle for the calcilytic approach includes a study in osteopenic ovariectomized (OVX) rats in which oral administration of a calcilytic agent NPS-2143 (Gowen M, et al. (2000) J. Clin. Invest. 105:1595-1604) resulted in an increase in bone mass in the presence of an anti-resorptive agent. Intravenous bolus injection of NPS-2143 resulted in a transient increase in serum PTH compatible with the anabolic profile of the hormone. These results indicate that calcilytic agents can serve as a novel class of anabolic agents for the treatment of established osteoporosis.
Thus, the identification of compounds which demonstrate activity as calcium sensing receptor modulators, preferably calcium sensing receptor antagonists, would be of significant value for the treatment of diseases or disorders associated with abnormal bone or mineral homeostasis.